Response to adversity: molecular control of gene activation following genotoxic stress.

DNA damage leads to the induction of a variety of genes in mammalian cells. In this article we summarize recent works aimed at examining the specificity of the response and elucidating the molecular mechanisms by which DNA damage effects changes in gene expression. The response to DNA damage is controlled primarily at the level of transcription. Some of the inducible genes are members of the class of "immediate early" genes and encode transcriptional activators. These genes are induced by activators of protein kinase C, and most DNA damage-inducible genes are also activated by phorbol esters. Phorbol ester-response elements within the 5' region of several of these genes have been shown to play a role in mediating their induction in response to DNA damage. However, DNA damage-inducible transcripts that are not sensitive to phorbol esters have also been identified, indicating that there are additional mechanisms involved in such responses. Induction of many of the DNA damage-inducible genes appears to be dependent, at least in part, on protein kinases. These findings demonstrate considerable overlap between signal transduction pathways mediating cellular proliferation and the response to DNA damage.